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A Patient with Pontocerebellar Hypoplasia Type 6: Novel RARS2 Mutations, Comparison to Previously Published Patients and Clinical Distinction from PEHO Syndrome

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A Patient with Pontocerebellar Hypoplasia Type 6: Novel RARS2 Mutations, Comparison to Previously Published Patients and Clinical Distinction from PEHO Syndrome Journal Pre-proof A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome Viivi Nevanlinna, Svetlana Konovalova, Berten Ceulemans, Mikko Muona, Anni Laari, Taru Hilander, Katarin Gorski, Leena Valanne, Anna-Kaisa Anttonen, Henna Tyynismaa, Carolina Courage, Anna-Elina Lehesjoki PII: S1769-7212(18)30943-1 DOI: https://doi.org/10.1016/j.ejmg.2019.103766 Reference: EJMG 103766 To appear in: European Journal of Medical Genetics Received Date: 21 December 2018 Revised Date: 15 September 2019 Accepted Date: 15 September 2019 Please cite this article as: V. Nevanlinna, S. Konovalova, B. Ceulemans, M. Muona, A. Laari, T. Hilander, K. Gorski, L. Valanne, A.-K. Anttonen, H. Tyynismaa, C. Courage, A.-E. Lehesjoki, A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome, European Journal of Medical Genetics (2019), doi: https://doi.org/10.1016/j.ejmg.2019.103766. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Masson SAS. 1 1 A Patient with Pontocerebellar Hypoplasia Type 6: Novel RARS2 Mutations, Comparison to 2 Previously Published Patients and Clinical Distinction from PEHO Syndrome 3 4 Viivi Nevanlinna a,b , Svetlana Konovalova c, Berten Ceulemans d, Mikko Muona a,1, Anni Laari a,c , Taru 5 Hilander c, Katarin Gorski a,c , Leena Valanne e, Anna-Kaisa Anttonen a,f,g, Henna Tyynismaa c, f, h , 6 Carolina Courage a,c , Anna-Elina Lehesjoki a,c,f,* 7 8 aFolkhälsan Research Center, Helsinki, Finland 9 bFaculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland 10 cResearch Programs Unit, Molecular Neurology, University of Helsinki, Finland 11 dDepartment of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Belgium 12 eDepartment of Radiology, Hospital District of Helsinki and Uusimaa Medical Imaging Center, 13 University of Helsinki and Helsinki University Hospital, Helsinki, Finland 14 fDepartment of Medical and Clinical Genetics, Medicum, University of Helsinki, Finland 15 gLaboratory of Genetics, Helsinki University Hospital, Helsinki, Finland 16 hNeuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland 17 1Present address: Blueprint Genetics, Helsinki, Finland 18 *Corresponding author. Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, 19 00290, Helsinki, Finland; tel: +358 2941 25072; email: [email protected] 2 20 Abstract 21 Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy 22 caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase 23 enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive 24 Encephalopathy with oedema, Hypsarrhythmia and Optic atrophy). The proband presented with 25 severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, 26 acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and 27 delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but 28 sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing 29 revealed novel compound heterozygous variants in RARS2 , a missense variant affecting a highly 30 conserved amino acid and a frameshift variant with consequent degradation of the transcript 31 resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features 32 distinguishing the proband’s phenotype from PEHO syndrome were later appearance of hypotonia 33 and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with 34 more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO 35 syndrome patients. The study highlights the challenges in clinical diagnosis of patients with 36 neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI 37 findings. 38 39 Keywords 40 Pontocerebellar hypoplasia type 6, RARS2, PEHO syndrome, progressive cerebellar and cerebral 41 atrophy 3 42 Introduction 43 Pontocerebellar hypoplasia (PCH) is a group of neurodegenerative disorders with autosomal 44 recessive inheritance. Up to date 11 different subtypes have been described, with 17 causative 45 genes identified (van Dijk et al., 2018). Most of the subtypes are characterized by prenatal or 46 neonatal onset, global developmental delay and intellectual disability, microcephaly, hypoplasia 47 and variable atrophy of cerebellar cortex and/or brainstem. The specific neurological symptoms 48 and the severity of symptoms and brain loss vary between the subtypes (van Dijk et al., 2018). 49 Pontocerebellar hypoplasia type 6 (PCH6; MIM 611523) is a rare form of PCH first described in 50 2007 in three patients of a consanguineous Sephardic Jewish family (Edvardson et al., 2007). Since 51 then, altogether 32 patients in 18 families have been reported in the literature (for a detailed 52 summary of the patients and phenotypes, see Supplementary Table; Edvardson et al., 2007; Rankin 53 et al., 2010; Namavar et al., 2011; Glamuzina et al., 2012; Cassandrini et al., 2013; Kastrissianakis 54 et al., 2013; Joseph et al., 2014; Li et al., 2015; Lax et al., 2015; Nishri et al., 2016; Alkhateeb et al., 55 2016; Ngoh et al., 2016; van Dijk et al., 2017; Luhl et al., 2016; Zhang et al., 2018). Most PCH6 56 patients present with neonatal onset, hypotonia, microcephaly, seizures, severe intellectual 57 disability with lack of developmental milestones and progressive atrophy of cerebral cortex, 58 cerebellum and pons. The majority show a respiratory chain enzyme deficiency and elevated 59 lactate levels in blood or cerebrospinal fluid (CSF). Indeed, PCH6 may be distinguished from the 60 other PCH subtypes, which are highly variable clinically and neuroradiologically, by the presence of 61 elevated lactate concentration (van Dijk et al., 2018). 62 PCH6 is caused by biallelic mutations in RARS2 , a nuclear gene that encodes the mitochondrial 63 arginine-tRNA synthetase enzyme (mtArgRS) (Edvardson et al., 2007). Aminoacyl-tRNA synthetases 64 play a crucial role in protein translation as they catalyze the specific attachment of an amino acid 4 65 (aminoacylation) to its cognate tRNA. MtArgRS participates in the synthesis of all 13 mitochondrial- 66 encoded proteins by charging of mitochondrial tRNA-Arg, thus being an integral part of 67 mitochondrial protein translation machinery, participating in generation of complexes of oxidative 68 phosphorylation system, except complex II, which has a fully nuclear origin (Ibba and Soll, 2000). 69 PCH6 shows clinically some resemblance to PEHO syndrome (Progressive Encephalopathy with 70 oedema, Hypsarrhythmia and Optic atrophy; MIM 260565), characterized by neonatal hypotonia, 71 profound psychomotor retardation, infantile spasms with hypsarrhythmia and atrophy of optic 72 disks (Salonen et al., 1991). Patients present with typical dysmorphic features, such as narrow 73 forehead, epicanthic folds, short nose and open mouth, and edema of the face and limbs (Somer, 74 1993). Neuroimaging findings include demyelination and progressive atrophy of the cerebellar 75 cortex, brainstem and optic nerves. In the cerebellum, the inner granular layer is nearly totally 76 absent and Purkinje cells are deformed and disaligned (Haltia and Somer, 1993). 77 PEHO syndrome is inherited autosomal recessively and was recently shown to be caused in Finnish 78 patients by a homozygous missense mutation c.92C>T; p.Leu31Ser in ZNHIT3 , a gene encoding zinc 79 finger HIT domain-containing protein 3 (Anttonen et al., 2017). PEHO syndrome is enriched in the 80 Finnish population with an estimated incidence of 1:74 000 (Somer, 1993) and approximately 40 81 diagnosed patients. In other populations it is very rare, with less than 25 reported patients (Field 82 et al., 2003; Caraballo et al., 2011; Alfadhel et al., 2011) and only one patient with compound 83 heterozygous mutations in ZNHIT3 reported so far (Öunap et al., 2019). In the literature, patients 84 with symptoms closely resembling PEHO syndrome are more commonly reported. The clinical 85 presentation of patients with PEHO-like features, like those with PCH, is similar to that of PEHO 86 syndrome, but optic atrophy and typical neuroradiologic findings are usually absent or there is no 87 progression (Field et al., 2003; Longman et al., 2003; Chitty et al., 1996). Several genes underlying 5 88 phenotypes resembling PEHO have been described (Rankin et al., 2010; Anttonen et al., 2015; 89 Gawlinski et al., 2016; Langlois et al., 2016; Nahorski et al., 2016; Flex et al., 2016; Miyake et al., 90 2016; Zollo et al., 2017; Chitre et al., 2018). 91 We report a patient with the initial presenting features suggestive of PEHO syndrome with typical 92 dysmorphic features, epileptic spasms, optic
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